East Indian sandalwood oil has been valued for perfumery for thousands of years. The natural oil contains mostly santalol compounds that impart a soft, woody odor that is easy to adore but hard to reproduce. Unfortunately, the santalols cannot be manufactured economically. The fragrance industry has therefore identified synthetic substitutes that boast some of the odor qualities of sandalwood oil yet are more feasible to make and sell.
Several commercial products having such a sandalwood aroma derive from an aldol condensation of α-campholenic aldehyde (ACA) and methyl ethyl ketone (MEK). In general, aldol condensation reactions can be catalyzed by either acid or base. In one common method, described in U.S. Pat. No. 4,052,341, condensation and dehydration reactions proceed simultaneously in one pot using potassium hydroxide in methanol. The reaction occurs at both C1 and C3 of MEK to provide a mixture of ketones. Isomerization of α,β-unsaturated ketones to β,γ-unsaturated ketones under the reaction and distillation conditions further complicates the process. In all, five ketone products result, as shown in Scheme 1. Ketones 1, 2, 4, and 5, upon hydrogenation, provide the secondary alcohol isomers found in Sandalore™, a product of Givaudan.


Only methyl ketones 1 and 4 can be used as precursors for making Polysantol™ (a product of Firmenich, see U.S. Pat. No. 4,610,813), and Ebanol™ (from Givaudan, see U.S. Pat. No. 4,696,766), the principal components of which are shown in Scheme 2.
While the maximum obtainable yields of the various aldol condensation products are challenging to decipher from the references noted above, we conclude that the highest yield of ketone 1 obtained from ACA is about 60%, the highest combined yield of ketones 1 and 4 is about 62%, and the best combined yield of all condensation products (ketones 1-5) is about 75%. Catalysts other than alkali metal hydroxides have been used, but the product compositions differ or the yields of the desired products are lower.
While it is generally known that aldol condensation reactions can be effected in two successive steps with different catalysts (see, e.g., U.S. Pat. Nos. 5,840,992 and 6,833,481), such a process has not been suggested for the reaction of ACA and MEK. In the typical two-step process, a base is used to produce an aldol product, and an acid (e.g., sulfuric, phosphoric, or oxalic acid) catalyzes the dehydration. The two-step process appeared to be problematic because ACA and its derivatives readily undergo acid-catalyzed rearrangements to form the corresponding β-campholenic aldehyde derivatives (see, e.g., C. Cardenas and B. Kane, “Rearrangement of α-Campholenic Aldehyde,” in Proceedings of 11th ICEOFF, New Delhi, 12-16 Nov. 1989, pp. 37-41).
In sum, improved ways to make sandalwood aroma compounds are desirable. In particular, a better approach to aldol condensation products of ACA and MEK is needed. A valuable process would provide the highest possible yield of ketone 1, which is a common intermediate for synthetic sandalwood products, and the highest possible combined yield of methyl ketones 1 and 4, which are used to make the principal components of Ebanol and Polysantol. Ideally, the process would be easy to practice using conventional reagents and common equipment.